Abstract
BackgroundCell migration and invasion are essential processes for metastatic dissemination of cancer cells. Significant progress has been made in developing new therapies against oncogenic signaling to eliminate cancer cells and shrink tumors. However, inherent heterogeneity and treatment-induced adaptation to drugs commonly enable subsets of cancer cells to survive therapy. In addition to local recurrence, these cells escape a primary tumor and migrate through the stroma to access the circulation and metastasize to different organs, leading to an incurable disease. As such, therapeutics that block migration and invasion of cancer cells may inhibit or reduce metastasis and significantly improve cancer therapy. This is particularly more important for cancers, such as triple negative breast cancer, that currently lack targeted drugs.MethodsWe used cell migration, 3D invasion, zebrafish metastasis model, and phosphorylation analysis of 43 protein kinases in nine triple negative breast cancer (TNBC) cell lines to study effects of fisetin and quercetin on inhibition of TNBC cell migration, invasion, and metastasis.ResultsFisetin and quercetin were highly effective against migration of all nine TNBC cell lines with up to 76 and 74% inhibitory effects, respectively. In addition, treatments significantly reduced 3D invasion of highly motile TNBC cells from spheroids into a collagen matrix and their metastasis in vivo. Fisetin and quercetin commonly targeted different components and substrates of the oncogenic PI3K/AKT pathway and significantly reduced their activities. Additionally, both compounds disrupted activities of several protein kinases in MAPK and STAT pathways. We used molecular inhibitors specific to these signaling proteins to establish the migration-inhibitory role of the two phytochemicals against TNBC cells.ConclusionsWe established that fisetin and quercetin potently inhibit migration of metastatic TNBC cells by interfering with activities of oncogenic protein kinases in multiple pathways.
Highlights
Cell migration and invasion are essential processes for metastatic dissemination of cancer cells
We demonstrated that fisetin and quercetin effectively reduced migration and matrix invasion of triple negative breast cancer (TNBC) cells in vitro and TNBC cell metastasis in zebrafish
Inhibitory effects of phytochemicals on migration and matrix invasion of TNBC cells In a previous study, we examined the potential of 20 phytochemicals to block migration of two metastatic TNBC cell lines and identified fisetin and quercetin as the most effective compounds [13]
Summary
Cell migration and invasion are essential processes for metastatic dissemination of cancer cells. Therapeutics that block migration and invasion of cancer cells may inhibit or reduce metastasis and significantly improve cancer therapy This is more important for cancers, such as triple negative breast cancer, that currently lack targeted drugs. Despite potential benefits of blocking cancer cell migration to prevent metastasis, the majority of existing therapeutics are only designed to kill proliferating cancer cells or suppress active oncogenic signaling These therapies show some initial success against tumor growth, they have limited or no efficacy against metastasis. Disrupting formation of membrane protrusions and actin polymerization by targeting an actin-related protein complex subunit using benproperine blocked migration of TNBC cells in vitro and metastasis in mice [12] These promising studies demonstrated that inhibition of cell migration may be used as a therapeutic strategy against cancer metastasis and highlighted the need for novel anti-metastatic compounds
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